Process for preparing 1-substituted 4-cyano-1,2,3-triazoles

ABSTRACT

The invention relates on the one hand to a novel preparation of compounds of the formula (I)                    
     in which R 1  is an aromatic or heteroaromatic radical, aromatic-aliphatic or heteroaromatic-aliphatic radical, a heterocyclic radical, a cycloaliphatic radical, a cycloaliphatic-aliphatic radical or an aliphatic radical, 
     and on the other hand to novel compounds of the formula (I).

This is a division of U.S. patent application Ser. No. 09/214,698,having a 371 date of Jan. 8, 1999, now issued as U.S. Pat. No. 6,156,907which is a 371 of International Application No. PCT/EP97/03671, filedJul. 10, 1997.

BACKGROUND OF THE INVENTION

1-Substituted 1H-1,2,3-triazoles are widely used industrially. Forexample, the European Patent Applications with the publication nos.114347 A2 (EP 114347) and 199262 A1 (EP 199262) describe appropriatetriazoles having anticonvulsive action. Compounds of this type areprepared, for example, by reaction of an arylalkyl azide with an alkynederivative followed, if desired, by subsequent chemical conversions.Actual embodiments can be seen, for example, from the working examplesof EP 199262 and EP 11 4347.

It is the aim of a variety of efforts to develop for pharmaceuticalactive ingredients production processes which are easy to manipulate andeconomical, result in high yields and ecologically have as fewobjections as possible.

The invention relates to a novel process for the preparation of1-substituted 1H-1,2,3-triazole-4-carbonitriles, to novel intermediatesand to their use for the production, for example, of pharmaceuticalactive ingredients.

DESCRIPTION OF THE INVENTION

The invention relates on the one hand to a novel preparation ofcompounds of the formula (I)

in which R₁ is an aromatic or heteroaromatic radical, aromatic-aliphaticor heteroaromatic-aliphatic radical, a heterocyclic radical, acycloaliphatic radical, a cycloaliphatic-aliphatic radical or analiphatic radical, and on the other hand to novel compounds of theformula (I).

An aromatic radical is, for example, mono- or bicyclic carbocyclic arylwhich is unsubstituted or mono- or polysubstituted, such as di- ortrisubstituted, for example phenyl, naphthyl or biphenylyl.

A heteroaromatic radical is, for example, mono- bi- or tricyclicheteroaryl, for example a 5- or 6-membered and monocyclic radical, whichcontains-up to and including four identical or different heteroatoms,such as oxygen, sulfur or nitrogen, preferably 1, 2, 3 or 4 nitrogenatoms, an oxygen or a sulfur atom.

Suitable 5-membered heteroaryl radicals are, for example, monoaza-,diaza-, triaza-, tetraaza-, monooxa- or monothiacyclic heteroarylradicals, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, furyl and thienyl, while possible 6-membered radicals are,in particular, pyridyl radicals.

In an aromatic-aliphatic radical, the aromatic moiety, for example, hasthe meaning which is indicated above for aromatic radicals, while analiphatic radical is, for example, lower alkyl, lower alkenyl or loweralkynyl. An aromatic-aliphatic radical is, for example, phenyl-loweralkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, furthermorenaphthyl-lower alkyl.

In a heteroaromatic-aliphatic radical, the heteroaromatic moiety, forexample, has the meaning which is indicated above for heteroaromaticradicals, while an aliphatic radical is, for example, lower alkyl, loweralkenyl or lower alkynyl. A heteroaromatic-aliphatic radical is, forexample, pyridyl-lower alkyl.

A heterocyclic radical is, for example, a 5- or 6-membered monocyclic ora bi- or tricyclic radical which contains up to and including fouridentical or different heteroatoms, such as nitrogen, oxygen or sulfur,preferably one, two or three nitrogen atoms, a sulfur and an oxygenatom. It is also possible for one or two benzene rings to be fused to anappropriate heterocyclic radical. A heterocyclic radical of this type,for example, is a partially hydrogenated 2-oxobenzazepine, such as2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine.

A cycloaliphatic radical is, for example, cycloalkyl or furthermorecycloalkenyl, which in each case are unsubstituted or mono- orpolysubstituted, e.g. disubstituted, e.g. by lower alkyl, carboxyl orlower alkoxycarbonyl. A cycloaliphatic-aliphatic radical is, forexample, cycloalkyl-lower alkyl or furthermore cycloalkenyl-lower alkyl.

An aliphatic radical is, for example, lower alkyl, lower alkenyl orfurthermore lower alkynyl, which are unsubstituted or in each casemono-or polysubstituted, e.g. disubstituted, e.g. by halogen, by free oresterified or amidated carboxyl, such as lower alkoxycarbonyl, carbamoylor mono- or di-lower alkylated carbamoyl, by hydroxyl which can also beetherified, by S(O)_(m)—R⁰ or by a hydrocarbon radical, such as loweralkyl, lower alkenyl or lower alkynyl, which in turn can beunsubstituted or substituted, for example by halogen or hydroxyl; mbeing 0, 1 or 2 and R⁰ being an aliphatic radical. Etherified hydroxylis, in particular, lower alkoxy or lower alkenyloxy, furthermorephenyl-lower alkoxy and phenoxy.

Aromatic and heteroaromatic radicals can be unsubstituted or mono- orpolysubstituted, e.g. di- or trisubstituted, for example by substituentsselected from: halogen, hydroxyl which can also be etherified,S(O)_(m)—R⁰ and a hydrocarbon radical which in turn can be unsubstitutedor substituted, for example by halogen or hydroxyl; m being 0, 1 or 2and R⁰ being an aliphatic radical.

If not defined differently, the general definitions used above and belowhave the following meanings:

The expression “lower” means that appropriate groups and compounds ineach case in particular contain up to and including 7, preferably up toand including 4, carbon atoms.

Naphthyl is 1- or 2-naphthyl.

Biphenylyl is 2-, 3- or, in particular, 4-biphenylyl.

Pyrrolyl is, for example, 2- or 3-pyrrolyl. Pyrazolyl is 3- or4-pyrazolyl. Imidazolyl is 2- or 4-irmidazolyl. Triazolyl is, forexample, 1H-1,2,4-triazol-2-yl or 1,3,4-triazol-2-yl. Tetrazolyl is, forexample, 1,2,3,4-tetrazol-5yl, furyl is 2- or 3-furyl and thienyl is 2-or 3-thienyl, while pyridyl can be 2-, 3- and 4-pyridyl.

Lower alkyl is in particular C₁-C₇alkyl, e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and furthermoreincludes corresponding pentyl, hexyl and heptyl radicals. C₁-C₄alkyl ispreferred.

Lower alkenyl is in particular C₃-C₇alkenyl and is for example,2-propenyl or 1-, 2- or 3-butenyl. C₃-C₅alkenyl is preferred.

Lower alkynyl is in particular C₃-C₇alkynyl and is preferably propargyl.

Phenyl lower alkyl is in particular phenyl-C₁-C₄alkyl and is preferablybenzyl, 1- and 2-phenethyl, while phenyl-lower alkenyl and phenyl-loweralkynyl are in particular phenyl- C₃-C₅alkenyl and -alkynyl, inparticular 3-phenylallyl and 3-phenylpropargyl.

Naphthyl-lower alkyl is in particular naphthyl-C₁-C₄alkyl and is, forexample, 1- or 2-naphthylmethyl, -ethyl, -n-propyl or -n-butyl.

Pyridyl-lower alkyl is in particular pyridyl-C₁-C₄alkyl and is, forexample, 2-, 3- or 4-pyridylmethyl, -ethyl, -n-propyl or -n-butyl.

Cycloalkyl is, for example, C₃-C₈cycloalkyl, which can be unsubstitutedor substituted, for example by lower alkyl and is, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is in particular C₃-C₇cycloalkenyl and is preferablycyclopent-2-enyl, cyclopent-3-enyl, cyclohex-2-enyl and cyclohex-3-enyl.

Cycloalkyl-lower alkyl is in particular C₃-C₈cycloalkyl-C₁-C₄alkyl andis, for example, cyclopentyl- or cyclohexylmethyl or -ethyl, whilecycloalkyl-lower alkenyl is in particular C₃-C₈cycloalkyl-C₃-C₄alkenyland is, for example, cyclopentyl- or cyclohexylprop-2-enyl orcyclo-2-butenyl.

Lower alkoxy is in particular C₁-C₇alkoxy and is, for example, methoxy,ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy,sec-butyloxy, tert-butyloxy and furthermore includes correspondingpentyloxy, hexyloxy and heptyloxy radicals. C₁-C₄alkoxy is preferred.

Lower alkenyloxy is in particular C₃-C₇alkenyloxy and is, for example,allyloxy or but-2-enyloxy or but-3-enyloxy. C₃-C₅alkenyloxy ispreferred.

Phenyl-lower alkoxy is in particular phenyl-C₁-C₄alkoxy, such asbenzyloxy, 1- or 2-phenylethoxy, 3-phenylpropyloxy or 4-phenylbutyloxy.

Lower alkoxycarbonyl is in particular C₂-C₈alkoxycarbonyl and is, forexample, methoxy-, ethoxy-, propyloxy- or pivaloyloxycarbonyl.C₂-C₅alkoxycarbonyl is preferred.

Halogen is in particular fluorine, chlorine or bromine, and furthermoreincludes iodine.

Japanese Patent Application J 56 127-363 describes a synthesispossibility for 1-substituted 1H-1,2,3-triazole-4-carbonitrile.Accordingly, the preparation of triazoles of this type takes placeaccording to the following two-stage reaction scheme:

In this case, R′, inter alia, can also be cyano and X can be halogen,such as chlorine or bromine. However, only reactions with brominederivatives of the formula (2) are exemplified. Actual reactions whichlead to compounds (3) and (4) in which R′ is cyano are described just aslittle in the working examples.

The procedure described in J 56 127-363 has the following disadvantages:On the one hand it is clearly a process to be carried out in twoseparate steps, in which the formation of the correspondingdihydrotriazoles (3) is extremely time-consuming, also theseintermediates must be isolated first before they can react further inthe second step. Thus appropriate reactions are described whose firststage is complete only after 4 days to 3 weeks, before the next step cantake place. This procedure is too troublesome and complicated for aproduction process.

In contrast, the process according to the invention proves clearlysuperior. Thus the formation of compounds of the formula (I) is carriedout in one step and in one reaction vessel without it being necessary toisolate intermediates. Furthermore, when using the reaction according tothe invention high yields are already attained after approximately 24hours.

The process according to the invention is characterized by the followingreaction equation:

the variable R₁ being defined as indicated above.

The invention relates in particular to the preparation of compounds ofthe formula (I) in which R₁ is phenyl, naphthyl, biphenylyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, pyridyl,phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl,naphthyl-lower alkyl, pyridyl-lower alkyl, a partially hydrogenated2-oxobenzazepine, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl orcycloalkenyl-lower alkyl, and also lower alkyl, lower alkenyl or loweralkynyl which are unsubstituted or in each case mono- or polysubstitutedby substituents selected from halogen, carboxyl, lower alkoxycarbonyl,carbamoyl, mono- or di-lower alkylated carbamoyl, hydroxyl, loweralkoxy, lower alkenyloxy, phenyl-lower alkoxy and phenoxy; it beingpossible for aromatic and heteroaromatic radicals to be unsubstituted ormono- or polysubstituted by substituents selected from: halogen, loweralkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, S(O)_(m)—R⁰, mbeing 0, 1 or 2 and R⁰ being lower alkyl, lower alkenyl andloweralkynyl, which are unsubstituted or in each case mono- orpolysubstituted by substituents selected from halogen, hydroxyl, loweralkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, carboxyl andlower alkoxycarbonyl.

The invention relates in particular to the preparation of compounds ofthe formula (I) in which R₁ is phenyl-lower alkyl, phenyl-lower alkenyl,phenyl-lower alkynyl, naphthyl-lower alkyl, pyridyl-lower alkyl, apartially hydrogenated 2-oxobenzazepine, cycloalkyl-lower alkyl,cycloalkenyl-lower alkyl or lower alkyl which is substituted by carboxylor lower alkoxycarbonyl; it being possible for aromatic andheteroaromatic radicals to be unsubstituted or mono- or polysubstitutedby substituents selected from: halogen, lower alkyl, lower alkenyl,lower alkynyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy,phenoxy and S(O)_(m)-R⁰, R⁰ being lower alkyl, lower alkenyl or loweralkynyl, and m being 0, 1 or 2.

The invention relates in particular to the preparation of compounds offormula (I) in which R₁ is 2,3,4,5-tetrahydro-1H-2-oxobenzazepin-1-yl orlower alkyl which is substituted by lower alkoxycarbonyl.

The invention relates in particular to the preparation of compounds ofthe formula (I) in which R₁ is phenyl- C₁-C₄alkyl substituted by loweralkyl, halogen and/or trifluoromethyl.

The invention relates in particular to the preparation of compounds ofthe formula (I) in which R₁ is benzyl substituted by lower alkyl,halogen and/or trifluoromethyl.

The invention relates in particular to the preparation of compounds ofthe formula (I) in which R₁ is 2-fluorobenzyl, 2-chloro-6-fluorobenzylor 2,6-difluorobenzyl.

The invention relates primarily to the preparation of4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole.

The invention relates in particular to the preparation of theN-substituted 4-cyano-1 H-1,2,3-triazole compounds mentioned in theworking examples.

The reaction according to the invention of the azide (Ia) with2-chloroacrylonitrile (Ib) to give a compound of the formula (I)comprises working in a two-phase system. The two-phase system consistsof an organic and an aqueous phase. The organic phase consistsessentially of the starting materials of the formulae (Ia) and (Ib), ifdesired in the presence of an organic solvent or diluent. The hydrogenchloride formed in the reaction is poorly soluble in this phase.

Appropriate organic solvents or diluents are, for example: aproticsolvents, for example weakly basic amides, such as dimethylformamide, oraliphatic, araliphatic and aromatic hydrocarbons or ethers, for exampleC₆-C₁₀alkanes or lower-alkylated benzene, such as xylene or toluene, ordi-lower alkyl ethers, such as dibutyl ether, anisole, or cyclic ethers,such as dioxane.

The hydrogen chloride should be readily soluble, but the startingmaterials poorly soluble, in the aqueous phase. Advantageously theaqueous phase consists of water.

Primarily, the two-phase system is formed from the organic phase,consisting of the starting materials (Ia) and (Ib), and from water.

The results shown in Table 2 of the working examples illustrate that thebest yields are attained in the two-phase system consisting on the onehand of the starting materials and on the other hand of water.

2-Chloroacrylonitrile can polymerize both under acidic and basic;conditions. On reaction of an azide of the formula (Ia) with2-chloroacrylonitrile, hydrogen chloride is released, i.e. a stronglyacidic medium results, which favors such a polymerization. This is alsothe case when an organic solvent is added, i.e. only one liquid phase ispresent. Additionally, the reaction is slowed down by dilution, the moreorganic solvent used. These disadvantages can be avoided if a two-phasesystem is used instead of a single-phase organic system. The azide ofthe formula (Ia) forms with 2-chloroacrylonitrile one, concentratedphase, while primarily water is the second phase. During the reactionresulting hydrogen chloride is continuously extracted into the aqueousphase and thus reduces the danger of the polymerization of2-chloroacrylonitrile. Moreover, the greatest possible reaction rate isattained in the two-phase system.

The amount of water should at least be proportioned so that the hydrogenchloride released in the reaction is soluble in the aqueous phase.

Per mole of compound of formula (Ia), preferably approximately 1 toapproximately 2 mol, primarily approximately 1.5 mol, of2-chloroacrylonitrile (1b) are employed. As the results presented inTable 1 of the working examples show, approximately 1.5 mol equivalentsof 2-chloroacrylonitrile are sufficient for an optimum yield. Thus inthe preparation of 4-cyano-2.6-difluorobenzyl-1H-1,2,3-triazole with areaction time of approximately 24 hours a desirable yield of over 90% oftheory is attained.

The reaction according to the invention is carried out, for example, ina temperature range from approximately 20° C. to approximately 85° C.,in particular from approximately 60° C. to approximately 85° C.,primarily from approximately 75° C. to approximately 85° C.

The invention furthermore relates to novel compounds of the formula (I).

The invention primarily relates to the compound4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole.

The invention furthermore relates to the use of a compound of theformula (I) for the production of a pharmaceutical active ingredient,for example of the resulting products according to EP 114347 and EP199262. Especially the resulting compounds of the claims of bothpublished patent applications are herewith incorporated by referenceinto the instant specification. The corresponding preparation ofcompounds of this type starting from compounds of the formula (I) iscarried out, for example, in a manner known per se. For example, thenitrites of the formula (I) can thus be converted by hydrolysis into thecorresponding carboxamides and these can be converted by furtherhydrolysis into the corresponding carboxylic acids.

The invention relates primarily to the use of the compound4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole for the production of apharmaceutical active ingredient, especially for the manufacture of1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-carboxamide or of apharmaceutically acceptable salt thereof.

The following examples serve to illustrate the present invention, butare not intended to restrict this in any case.

Example 1 4-Cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2.6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile(17.73 g) and water (125 ml) is stirred at about 80° C. for 24 hours.Excess 2-chloroacrylonitrile is distilled off by raising the externaltemperature to about 130° C. The semi-solid mixture is cooled to about40° C. and the suspension is treated with cyclohexane (50 ml), broughtto about 20° C. and stirred for about 2 hours. The product is isolatedby filtration, washed with cyclohexane (75 ml) and then with water (50ml). The moist product is mixed with water (100 ml), the suspension isfiltered and the product is washed with water (50 ml) and dried in vacuoat about 60° C. Yield: 38.04 g=86%.

Example 2 4-Cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile(17.73 9) and water (125 ml) is stirred at about 80° C. for 48 hours.Excess 2-chloroacrylonitrile is distilled off by raising the externaltemperature to about 130° C. The semi-solid mixture is cooled to about40° C. and the suspension is treated with cyclohexane (50 ml), broughtto about 20° C. and stirred for about 2 hours. The product is isolatedby filtration, washed with cyclohexane (75 ml) and then with water anddried in vacuo at about 60° C.

Yield: 40.91 g=93%.

Example 3 4-Cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 9), 2-chloroacrylonftrile(26.6 g) and water (125 ml) is stirred at about 70° C. for 24 hours.Excess 2-chloroacrylonitrile is distilled off by raising the externaltemperature to about 130° C. The mixture is cooled to about 95° C. andthe product is crystallized by seeding. After cooling to about 40° C.,the suspension is treated with cyclohexane (50 ml) and brought to about20° C., and the product is isolated by filtration, washed withcyclohexane (75 ml) and then with water and dried in vacuo at about 60°C. Yield: 36.38 g=82.6%.

Example 4 4-Cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile(26.6 g) and water (125 ml) is stirred at about 80° C. for 24 hours.Excess 2-chloroacrylonitrile is distilled off by raising the externaltemperature to about 130° C. The mixture is cooled to about 95° C. andthe product is crystallized by seeding. After cooling to about 40° C.,the suspension is treated with cyclohexane (50 -ml) and brought to about20° C., and stirred for about 2 hours. The product is isolated byfiltration, washed with cyclohexane (75 ml) and then with water anddried in vacuo at about 60° C. Yield: 43.13 g=98%.

Example 5 4-Cyano-1-(2.6-difluorobenzyl-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (6.75 g), 2-chloroacrylonitrile(7.0 g) and water (20 ml) is stirred at about 80° C. for 12 hours.Excess 2-chloroacrylonitrile is distilled off by raising the externaltemperature to about 120° C. The mixture is cooled to about 20° C. andthe crystallized product is isolated by filtration and washed withwater. The moist product is dried in vacuo at about 60° C. Yield: 8.17g=93%. For purification, the product (8.17 g) is dissolved in toluene(40 ml) at 80° C. and treated with bleaching earth (0.24 g), and themixture is filtered hot. The filtrate is concentrated to about 20 ml andthe resulting crystal magma is stirred at 0° C. for 1 hour. Afterfiltering, washing with toluene and drying, a white product (7.72 g) ofm.p. 115.5-116.5° C. is obtained.

Example 6 4-Cyano-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile(35.46 g) and water (125 ml) is stirred at about 80° C. for 24 hours.Excess 2-chloroacrylonitrile is distilled off by raising the externaltemperature to about 130° C. The mixture is cooled to about 40° C. andthe suspension is treated with cyclohexane (50 ml), brought to about 20°C., and stirred for about 2 hours. The product is isolated byfiltration, washed with cyclohexane (75 ml) and then with water (50 ml).The moist product is mixed with water (100 ml), the suspension is theproduct is washed with water (50 ml) and dried in vacuo at about 60° C.Yield: 42.87 g=97%.

TABLE 1 Mol equivalent of Example 2-chloroacrylonitrile TemperatureReaction time Yield 1 1.0 80° C. 24 h 86% 2 1.0 80° C. 48 h 93% 3 1.570° C. 24 h 83% 4 1.5 80° C. 24 h 98% 5 2.0 80° C. 12 h 93% 6 2.0 80° C.24 h 97%

Example 7 4-Cyano-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 g) and 2-chloroacrylonitrile(26.6 g) is stirred at about 80° C. for 24 hours. n-Heptane (125 ml) isallowed to run in, and unreacted 2chloroacrylonitrile and2,6-difluorobenzyl azide as well as n-heptane are distilled off(distillate 50 ml) by raising the external temperature to about 130° C.The mixture is cooled to about 20° C. and the suspension is stirred atabout 20° C. for 1 hour. The product is isolated by filtration andwashed with n-heptane (100 ml). The product is dried in vacuo at about60° C. Yield: 31.55 g=71.6% (beige powder).

Example 8 4-Cyano-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile(26.6 g) and n-heptane (125 ml) is stirred at about 80° C. for 24 hours,whereby a suspension results. Unreacted 2-chloroacrylonitrile and2,6-difluorobenzyl azide as well as n-heptane are distilled off(distillate 25 ml) by raising the external temperature to about 130° C.The mixture is cooled to about 20° C. and the suspension is stirred atabout 20° C. for about 2 hours. The product is isolated by filtration,washed with n-heptane (100 ml) and dried in vacuo at about 60° C. Yield:20.45 g=46.4% (beige powder).

Example 9 4-Cyano-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile(26.6 g) and toluene (125 ml) is stirred at about 80° C. for 24 hours.Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well astoluene are distilled off (distillate 100 ml) by raising the externaltemperature to about 130° C. After cooling to 80° C., n-heptane (100 ml)is allowed to run in. The mixture is cooled to about 20° C. and thesuspension is stirred at about 20° C. for 1 hour. The product isisolated by filtration and washed with n-heptane (100 ml). The productis dried in vacuo at about 60° C. Yield: 22.31 g=50.7% (beige powder).

Example 10 4-Cyano-(2,6-difluorobenzyl-1H-1,2,3-triazole

A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile(26.6 g) and absolute ethanol (125 ml) is stirred at about 77° C. for 24hours. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide aswell as ethanol are distilled off (distillate 100 ml) by raising theexternal temperature to about 130° C. After cooling to 70° C., water(100 ml) is allowed to run in dropwise at 70-60° C. The mixture isseeded, cooled to about 20° C. and the suspension is stirred at about20° C. for about 1 hour. The product is isolated by filtration andwashed with cyclohexane (100 ml) and then with water (100 ml). Theproduct is dried in vacuo at about 60° C. Yield: 17.73 g=40.3% (palebeige powder).

Example 11 4-Cyano-(2,6-difluorobenzyl)-1H-1,2,3-triazole

A mixture of 2,6-difluorbenzyl azide (34.2 g), 2-chloroacrylonitrile(26.6 g) and N,N-dimethylformamide (125 ml) is stirred at about 80° C.for 24 hours. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzylazide as well as N,N-dimethylformamide are distilled off (distillate 100ml) by raising the external temperature to about 130° C. and graduallyevacuating to about 100 mbar. After cooling to 100° C., water (100 ml)is allowed to run in. The crystallization of the product is initiated byseeding the brown emulsion. The mixture is cooled to about 20° C. andthe suspension is stirred at about 20° C. for 30 minutes. The product isisolated by filtration and washed with water (100 ml). The product isdried in vacuo at about 60° C. Yield: 34.40 g=78.1% (beige crystals).

TABLE 2 Mol equivalent of Ex- 2-chloro- Temp- Reaction ample Solventacrylonitrile erature time Yield 4 water*) 1.5 80° C. 24 h 98% 7 without1.5 80° C. 24 h 72% 8 n-heptane 1.5 80° C. 24 h 46% 9 toluene 1.5 80° C.24 h 51% 10 ethanol 1.5 77° C. 24 h 40% 11 dimethylform- 1.5 80° C. 24 h78% amide *)First phase = Starting materials; second phase = water

Example 12 1-Benzyl-4-cyano-1H-1,2,3-triazole

A mixture of benzyl azide (1.33 g) and 2-chloroacrylonitrile (1.75 g) inwater (5 ml) is stirred at about 80° C. for 22 hours, then excess2-chloroacrylonitrile is distilled off in vacuo. The mixture is cooledto room temperature and the precipitated product is isolated byfiltration and washed with water. After drying, the product is obtainedin a yield of 1.66 g=90% of theory m.p. 78-79° C. (recrystallizationfrom toluene/hexane).

Example 13 4-Cyano-1-(4-cyanobenzyl)-1H-1,2,3-triazole

A mixture of 4-cyanobenzyl azide (0.8 g) and 2-chloroacrylonitrile (0.889) in water (5 ml) is stirred at about 80° C. for 20 hours. Excess2-chloroacrylonitrile is distilled off in vacuo, the mixture is cooledto room temperature and the precipitated product is isolated byfiltration and washed with water. The product (yield 0.92 g; 88% oftheory) of m.p. 93.5-94° C. (recrystallization from ethylacetate/toluene) is obtained after drying.

Example 143-(4-Cyano-1H-1,2,3-triazol-1-yl)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine

A mixture of 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine (1.01 g)and 2-chloroacrylonitrile (0.95 g) in water (5 ml) is stirred at about80° C. for 18 hours. Excess 2-chloroacrylonitrile is distilled off invacuo, and the precipitated product is filtered off, washed with waterand dried (yield 1.1 g; 87% of theory), m.p. 214-216° C.(recrystallization from ethyl acetate/toluene).

Example 15 Ethyl(4-cyano1H-1,2,3-triazol-1yl)acetate

A mixture of ethyl 2-azidoacetate (1.29 g) and 2-chloroacrylonitrile(1.75 g) in water (10 ml) is stirred at about 80° C. for 16 hours. Aftercooling, the product is extracted with dichloromethane and theconcentrated extract is purified by means of column chromatography onsilica gel 60 (6 g; eluent toluenelethyl acetate=4:1). The purifiedproduct (yield 1.21 g; 67% of theory) of m.p. 47-48° C.(recrystallization from toluene/hexane) is obtained after concentratingthe eluate and drying.

Example 16 Ethyl2-(4-cyano-1H-1,2,3-triazol-1-yl)-4-phenyl-(2S)-butyrate

A mixture of ethyl 2-azido-4-phenyl-(2S)-butyrate (2.33 g) and2-chloroacrylonitrile (1.75 g) in water (25 ml) is stirred at about 80°C. for 23 hours. After cooling, the product is extracted with tolueneand purified by column chromatography (30 g of silica gel 60; eluenttoluene). The purified product is obtained as a yellowish oil (yield1.84 g; 65% of theory) and characterized by ¹H-NMR spectrum (CDCl₃). δvalue: 1.29 (*H; t; J=7 Hz); 2.40-2.67 (4H, m); 4.20 (2H, q, J=7 Hz);5.39 (1H, m); 7.10 (2H, dxd, J₁=6.6 Hz, J₂≦1.5 Hz); 7.24 (1H, txt,J₁=6.6 Hz, J₂≦1.5 Hz); 7.31 (2h, m); 8.21 (1H, s).

Example 17 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazol-4-carboxamide

A mixture of 2,6-difluorobenzylazide (9,22 g), 2-chloroacryonitrile(6,68 g) and water is stirred at about 82° C. for about 24 hours.2-Chloroacrylnitrile is distilled off by raising the externaltemperature to about 113° C. excess. The mixture is cooled to about 40°C. and toluene (10 ml) is added. Within about 40 minutes at about 80° C.sodium hydroxide (5,5 ml—30%) is added the amide being crystallized. Byraising the external temperature to 112° C., toluene is distilled off.The suspension is cooled to 20° C. and the product is isolated byfiltration, washed with water (200 ml) and dried at about 60° C. invacuo.

What is claimed is:
 1. The compound4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole.